The present discussion relates to apparatus and methods useful in industrial-scale chromatography, e.g. large-scale preparative purification of fine chemicals and pharmaceuticals, including biological products. It is not concerned with laboratory-scale apparatus. Conventionally an industrial-scale chromatography column has a cylindrical axially-vertical column tube with top and bottom end cells, each of which provides a strong backing plate with a fluid inlet/outlet and support for a layer of mesh, sinter or other fluid-permeable retaining material which lets process liquid flow into and out of the chromatography space while retaining the bed of particulate chromatography medium. To provide adjustability and control of bed height and bed compression, at least the top end cell is usually made in the form of a piston slidable in the column tube interior. The bottom end cell may also be a piston but more usually is a fixed plate bolted against a bottom end flange of the column tube. Typically this bottom plate acts as a support for the column as a whole, being itself supported on legs or some other stand arrangement leaving clearance for outlet pipework projecting beneath the bottom end cell.
Various mechanisms are known for controlling the position of the piston end cell. The structure supporting the piston must move into the column interior behind the piston, and so must be smaller than the column diameter. Usually metal spacer posts are fixed to the back of the end plate and extend up axially—to a distance corresponding roughly to the length of adjustment anticipated—to a lifting ring which is connected in turn down to an external drive and support mechanism able to move the end cell piston, via the spacer posts, relative to the fixed mounting. For example a set of lifting rods may extend up axially outside the column from the fixed mounting to the lifting ring. The lifting rods include (or are connected to) an axial drive, usually a mechanical threaded drive which may be hand-operated, to move the lifting ring up and down and thereby control the position of the end cell piston in the column. Because the piston is large, close-fitting and acts on a bed of fluid or particulate medium which may be packed, it is crucial that the rate of raising or lowering the piston be carefully equalised around the column and this requires care and time.
In the prior art, U.S. Pat. No. 5,681,474 describes a chromatography column in which the top end cell plunger is carried by three rods connected to hydraulic drive cylinders, operated from a central control to preserve alignment of the top cell as it is forced down onto the media bed, especially to achieve flow packing.
WO 00/00259 describes a column in which the top end cell can be fully retracted from the column tube by means of a set of threaded rods driven in rotation.
Columns marketed by Chromaflow in the mid 90's also featured hydraulic drives to move and if necessary withdraw upper and lower end cell plungers relative to the column tube.
From time to time in certain kinds of columns and processes it may be desirable or necessary to get access to the column interior for purposes other than filling or emptying particulate medium, especially since columns are now available which can do the latter through valved ports. In particular, column maintenance may require access to the inner parts of the end cells e.g. to remove their permeable retaining layers (mesh or sinter) and/or their seals, for cleaning, replacement or repair. For such access, the end cell must be withdrawn and separated from the column tube, either entirely or at least with enough clearance to carry out the operation in question, e.g. removal/insertion of a permeable layer element or seal. Typically access to the lower permeable element is by unbolting a lower column tube flange from the bottom end cell plate, and lifting the column tube up away from the plate sufficiently to unfasten and remove the permeable element sideways. Access to the permeable element of the top (piston) end cell is by lifting the piston right out of the column tube using the mechanism provided, sufficiently far for the permeable element to be moved in or out sideways.
The column elements being heavy, these operations normally have to be done with the aid of cranes, powered drives or by manual mechanisms with substantial mechanical advantage. For the same reason, alignment structures are used to keep the column and its end cells axially aligned as they are separated from each other as described. This avoids potential serious damage to precision components. The alignment and lifting structures cause significant obstructions around the tube, and need to be carefully laid out to provide sufficient clearance at some part of the circumference for insertion/removal of the permeable retaining elements if this is to be an operational requirement.
First, the basic elements of the apparatus are described with reference to FIGS. 1 and 2. A chromatography column consists essentially of a steel column tube 1 mounted on a bottom base plate 5, supported on the ground through a set of legs 51. The column tube has integral top and bottom flanges 11,12 projecting perpendicularly around its top and bottom edges. The base plate 5 consists of a lower support plate 52 with a flat upper surface and an inner contoured cell plate 53. The cell plate 53 has a contoured surface with an array of support projections and intervening conduits (not shown) on which a permeable element (lower end mesh) lies and is held in place by an array of fasteners. A multiport access valve 55 communicates with the space above the cell plate through a central orifice in the bottom plate 5 to enable unpacking of chromatography medium and collection of eluent in processing; this is all established technology. The bottom tube flange 12 seats down around the edge of the base plate 5, compressing peripheral seals and clamping the edge of the mesh, and is secured there by bolt or stud fasteners 57.
The top cell 6 likewise has a rigid flat backing plate 62 and an inner contoured cell plate 63 for supporting an end mesh (not shown), but unlike the bottom end cell is configured as a piston slidable inside the column tube. It is supported from above through a circumferentially-distributed array of vertical (axial) spacer rods 66 whose bottom ends are screwed rigidly into the cell's backing plate 62, while their top ends screwed up into the inner periphery of an annular adjuster flange 7. The adjuster flange 7, sometimes called a lifting ring, is spaced coaxially above the top column tube flange 11 and has the same OD but a smaller ID, so that it overhangs the column interior for securement to the spacer rods 66 that hold the piston 6.
Fluid communication through the top end cell 6 is through another central access valve 65, similar to that in the bottom plate 5. Among other functions, these access valves enable particulate medium to be packed into and unpacked from the bed space of the column as a slurry, without opening the column.
Three vertical guide rods 71 have their top ends fixedly threaded into the adjuster flange 7 at spaced locations (see views (b)). Each of these guide rods 71 descends with clearance through a set of aligned guide holes through the upper and lower column tube flanges 11,12 and the periphery of the column base 5.
Hydraulic drive cylinders 8 are mounted vertically on the underside of the outer base plate 52, and their driven rods 81 extend up through further sets of aligned holes in the base 5, upper and lower column tube flanges 11,12 and adjuster flange 7. Each lifting rod 81 is threaded near its top and has a pair of locating nuts 82 to either side of the adjuster flange 7 for fixing the flange to the rod 81 at a selected position. In this example there are three drive cylinders 8.
Further connecting structure is provided by a set of three vertical tie bars 73. These are short threaded rods received in openings through the adjuster flange 7 and top column tube flange 11, with respective pairs of locking nuts 74,75 to fix the location of each of these engagements.
Operation of the drive cylinders 8 directly raises or lowers the adjuster flange 7, to a height determined by the location of the drive rod locknuts 82. The top end cell piston 6, being rigidly connected to the adjuster flange 7 through the spacer rods 66, is raised or lowered correspondingly. If the tie rods 73 are locked by their locating nuts 74,75 to both the adjuster flange 7 and column tube flange 11, the drive rods 81 will lift the column tube 1 as well provided that it has first been released from the base 5 by releasing the studs 57.
The following description of maintenance steps can now be followed.
To remove or gain access to the lower mesh or seals, the hydraulic cylinders are fully retracted to set the piston 6 to its lowermost position. The studs 57 holding the column tube 1 to the base 5 are removed. The tie rods 73 are locked to the upper column tube flange 11. Refer to FIG. 2. The hydraulic cylinders are then extended raising the adjuster flange 7, column tube 1 and top cell 6 away from the base. The guide rods 71 slide through their aligned holes in the base to keep the components in line and protect the hydraulic lifts from lateral forces. In this condition the lower mesh can be detached from its mounting 53 and removed through the clearance between column tube 1 and base 5. Note in views (b) that the guide rods 71 are circumferentially spaced more widely to the right of the view, providing a larger opening there for passage of the mesh assembly.
Next, the known mode of removal of the upper mesh is described with reference to FIGS. 3, 4 and 5. Essentially the top piston 6 has to be lifted out above the column tube 1. To achieve this, the piston 6 is raised by the drives 8 to maximum operating height in the column, the tie rods 73 then being at full reach (FIG. 3). The tie rods are then locked at the adjuster flange 7 and tube flange 11, so that the adjuster flange 7 is supported fixedly by the column tube 1 and tie rods 73. The drive rods 81 can then be released from the flange 7, fully retracted and re-fastened with a new location on the flange 7 giving extra reach: see FIG. 4. The tie rods 73 are then fully released, and full advance of the hydraulic drives lifts the piston end cell 6 clear above the column tube 1 as seen in FIG. 5. The upper mesh can then be removed through the resulting clearance, between the two right-hand guide rods 71 which as before maintain the alignment of the components, and which by locking relative to the base 5 and or tube 1 support the piston 6 in its raised position. Throughout this operation the tube 1 preferably remains bolted to the base 5.
The described procedure and apparatus provide access to the two end cells without requiring overhead lifting equipment. Industrial columns can be very large and heavy; typically the column diameter is 500 mm or more. The illustrated column has a 1400 mm diameter and would be very difficult to manoeuvre without a powered lift.
The described apparatus and procedure have however the drawback that access to the upper mesh is difficult; it has to be removed at quite a distance above the ground. For such a large and delicate component this is a significant issue.
We also note the system described in WO 03/076923, which gets access to the top end cell piston by connecting the piston centrally to an overhead yoke. Once the piston has been lifted to the top of the column tube, this yoke can be released at one side and swung up and over to bring the piston (inverted) down beside the column. This gives lower access in the final position, but the swinging over of the piston would be a risky matter with a large column, so that this proposal is limited to smaller columns.